Therapeutic Advances in Medical Oncology最新文献

Background: Systemic therapy is a standard treatment option for pancreatic neuroendocrine neoplasms (Pan-NENs) with unresectable or metastatic disease. Streptozocin (STZ)-based chemotherapy is considered a standard treatment option for tumors with a high Ki-67 index or for cases refractory to molecular targeted agents. More recently, the combination of capecitabine and temozolomide (CAPTEM) therapy has emerged as a new treatment option.

Objectives: This study aimed to compare the efficacy, safety, and clinical outcomes between the STZ-based regimen and CAPTEM therapy in patients with unresectable or metastatic Pan-NENs.

Design: This was a single-center retrospective study of histologically confirmed Pan-neuroendocrine tumor (NET) patients treated with either STZ-based regimens or CAPTEM between November 2015 and June 2024.

Methods: We compared efficacy, safety, and clinical outcomes between the two regimens. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events were graded according to Common Terminology Criteria for Adverse Events version 5.0. The study was conducted in compliance with the STROBE guidelines.

Results: Of the 371 patients diagnosed with Pan-NENs, 47 received STZ-based regimen and 21 received CAPTEM therapy. In the NET-G1/G2 patients, the STZ group showed a significantly higher tumor shrinkage rate compared to CAPTEM therapy. Although no significant differences were observed in progression-free survival (PFS) or overall survival between the two groups, subgroup analysis showed that the median PFS in the STZ group was significantly longer than that in the CAPTEM group in NET G1/G2 patients. Renal dysfunction was the main adverse event in the STZ regimen group, while gastrointestinal symptoms were common in the CAPTEM therapy group; however, both were manageable.

Conclusion: Both STZ-based regimen and CAPTEM therapy are safe and effective treatment options for advanced Pan-NENs. STZ-based regimen was more beneficial in NET-G1/G2 patients, suggesting Ki-67 index and tumor grade may serve as indicators for treatment selection. Further prospective studies are warranted to validate these findings.

Radiation-induced normal tissue injuries (RITIs) are the main complications that can significantly limit the use of radiotherapy and affect clinical outcomes in patients with cancer. This article aims to review current literature on the role of proinflammatory cytokine interleukin (IL)-17A in different types of RITIs. While irradiation significantly increases IL-17A expression in normal tissues, activated IL-17A plays a dual role of both promoting and protecting against RITIs, depending on the tissue type. These novel findings have led to a strong interest in evaluating the therapeutic potential of targeting IL-17A/IL-17 receptor signals in RITIs in different normal tissues. Preliminary results from preclinical animal models have shown that blocking IL-17A/IL-17 receptor signaling after irradiation significantly reduces the pathogenesis of RITIs in the skin and lung but enhances it in the intestine and oral mucosa. However, the mechanisms underlying the tissue-dependent dual roles of IL-17A in RITIs remain elusive. Therefore, future studies focusing on the precise role and mechanism of IL-17A action in different RITIs are needed.

Background: Although considerable discoveries have been made in the genomic landscape of lung adenocarcinoma, to date, little is known regarding potential prognostic factors and altered pathways in resected squamous non-small-cell lung cancer (squamous-NSCLC).

Objective: We aimed to analyze the genomic background of prognostic outlier patients, selected based on a previously validated model, to assess differential genomics, and to investigate its relationship with prognosis.

Design: We conducted a retrospective study on three squamous-NSCLC cohorts, integrating next-generation sequencing (NGS)-based genomic profiling and NanoString expression analysis to identify molecular alterations associated with patient prognosis.

Methods: NGS analysis of somatic mutations (SM) and copy number variations (CNV) was performed by applying a 409-gene Comprehensive Cancer panel in the training set (Cohort #1) and a 56-gene customized panel in the validation set (Cohort #2). Genomic expression (NanoString) was further evaluated on an additional cohort (Cohort #3).

Results: Sixty and thirty-seven (n = 97) Caucasian patients with available tissue out of the original 176 and 46 (n = 222) samples were evaluated as training and validation cohorts, respectively. CNVs were the most frequent genomic events. Molecular alterations were distributed regardless of prognosis, except for DDR2 mutations in the good prognosis (GP) and SMAD4 loss in the poor prognosis (PP) group. The PI3KCA/mTOR axis represented the most frequently altered pathway (42%), with PI3KCA mutations and RICTOR high gain reported only in the PP group. A genomic expression analysis performed in Cohort #3 (n = 35) showed that a downregulation in the PI3K/AKT/mTOR pathway was mainly evident in the GP group of patients.

Conclusion: This integrated multi-step analysis identified potentially altered pathways with a biological impact on squamous-NSCLC oncogenesis, suggesting that the PI3KCA/mTOR pathway could affect the prognosis of resected SCC patients through both genomic aberrations and impaired expression.

Background: Changes in human epidermal growth factor receptor 2 (HER2) status following neoadjuvant chemotherapy (NAC) indicate tumor heterogeneity.

Objective: Investigating the prognostic impact of the transition between HER2-low and HER2-zero may help eliminate the confounding effects of heterogeneity, thereby clarifying the prognostic significance of HER2-low status.

Design: Retrospective analysis.

Methods: Data were collected from patients with HER2-negative, early-stage breast cancer who did not achieve a pathological complete response after NAC. Cox regression models and Kaplan-Meier survival curves were employed to analyze disease-free survival (DFS) and overall survival (OS).

Results: A total of 744 patients were included in the analysis, including 207 with HER2-zero and 537 with HER2-low pre-NAC. Among these, 46.9% (97/207) of the patients with HER2-zero transitioned to HER2-low, whereas 14.7% (79/537) of those with HER2-low transitioned to HER2-zero. Based on the HER2 status pre-NAC, there was no difference in prognosis between the HER2-zero and HER2-low groups. Patients with constant HER2-zero status had poorer OS than those who transitioned from HER2-zero to HER2-low (p = 0.025) in the hormone receptor-negative population, albeit no such result was observed in the hormone receptor-positive population. No significant difference in OS was observed between patients with constant HER2-low status and those who transitioned from HER2-low to HER2-zero. In addition, no significant differences were noted in the DFS across the groups. Multivariate analysis revealed that the constant HER2-zero status was associated with worse OS when compared with other HER2 statuses.

Conclusion: HER2 transitions between low and zero expressions were frequently observed after NAC, exhibiting heterogeneity of the HER2 expression. Except for the worst OS in the constant HER2-zero, hormone receptor-negative subgroup, no significant differences were observed in the DFS and OS with respect to the changes of HER2-zero and HER2-low groups. The prognostic significance of HER2-zero and HER2-low changes after NAC requires further exploration through prospective studies.

Background: Gallbladder cancer (GBC) represents a rare but aggressive malignancy, often diagnosed at an advanced stage. Although immune checkpoint inhibitors have improved outcomes in biliary tract cancers, GBC-specific evidence remains limited due to underrepresentation in pivotal clinical trials.

Objectives: To evaluate the real-world effectiveness and safety of durvalumab combined with gemcitabine and cisplatin (Durva + gemcitabine and cisplatin (GemCis)) compared to GemCis alone in patients with advanced GBC.

Design: Retrospective, multi-institutional cohort study.

Methods: Data were collected from the TriNetX Global Collaborative Network. Adults diagnosed with advanced GBC between January 2020 and January 2025 who received Durva + GemCis or GemCis as first-line therapy were included. Propensity score matching (1:1) was performed based on age, sex, race, metastatic sites, and tumor marker levels. The primary outcome was overall survival (OS), whereas secondary outcomes included adverse events (AEs).

Results: Among 2458 patients with advanced GBC, 130 received Durva + GemCis and 201 received GemCis. After matching, 111 patients per group were analyzed. Median OS was significantly longer in the Durva + GemCis group compared to the GemCis group (13.1 vs 8.5 months; log-rank p = 0.028). Most AEs were comparable between groups; however, malaise and fatigue were more frequently reported in the Durva group (28.8% vs 16.2%; hazard ratio: 1.98, 95% confidence interval: 1.11-3.53).

Conclusion: In this real-world study, the addition of durvalumab to GemCis was associated with improved OS in patients with advanced GBC, with a manageable safety profile. These exploratory findings should be interpreted with caution, underscoring the need for dedicated GBC-specific prospective trials.

Background: Immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), yet reliable biomarkers for predicting response remain limited. Neutrophil extracellular traps (NETs) may influence tumor immunity, but their clinical significance in NSCLC is unclear.

Objectives: To evaluate the predictive and prognostic value of NETs in advanced NSCLC patients treated with chemo-immunotherapy.

Design: A retrospective cohort study.

Methods: Pretreatment formalin-fixed paraffin-embedded biopsies from 46 stage IV NSCLC patients receiving first-line chemo-immunotherapy were analyzed by multiplex immunofluorescence to quantify NETs, CD8⁺ T cells, and cancer-associated fibroblasts (CAFs). Survival and correlation analyses were performed.

Results: High NETs' density was associated with shorter progression-free survival (PFS: 8 vs 20 months, p = 0.028) and overall survival (OS: 14.7 vs 29.8 months, p = 0.0046). NETs' levels inversely correlated with CD8⁺ T-cell density (R = -0.33, p = 0.025) and showed a trend toward positive correlation with CAFs (R = 0.27, p = 0.07). Poorer survival was observed when a high density of CAFs and CD8⁺ T cells was present within 30 µm of NETs. Multivariate Cox analysis confirmed high NETs as an independent prognostic factor.

Conclusion: NETs predict poor immunotherapy response and survival in advanced NSCLC and interact with CD8⁺ T cells and CAFs to potentially mediate resistance. NETs represent a promising biomarker and potential therapeutic target for enhancing immunotherapy efficacy in NSCLC.

Background: All stage III colon cancer (CC) patients are recommended adjuvant chemotherapy (ACT) after surgery, while over half are already cured by surgery alone. The prognostic biomarker circulating tumor DNA (ctDNA) could potentially guide the decision on whom to withhold ACT.

Objective: We assessed the cost-effectiveness of ctDNA-guided ACT de-escalation in stage III CC.

Design: A decision model "PATTERN-stageIII" simulates CC from diagnosis till death in surgically treated stage III patients.

Methods: We evaluated administering ACT in all patients (i.e., All ACT strategy), and three ACT de-escalation strategies by omitting ACT in patients who are (Strategy 1) both pT1-3N1 and ctDNA-negative, (Strategy 2) pT1-3N1, have no vascular invasion, and are ctDNA-negative, and (Strategy 3) pT1-2N1 and ctDNA-negative. For each strategy, costs, quality-adjusted life years (QALYs), and net monetary benefit were estimated. Sensitivity analyses assessed changes in ACT effectiveness and ctDNA-related parameters.

Results: In de-escalation strategies 1, 2, and 3, respectively, 52%, 61%, and 88% of patients were predicted to receive ACT, thereby losing 0.322, 0.237, and 0.034 QALYs per person. The "All ACT strategy" was preferred in terms of cost-effectiveness. Sensitivity analyses demonstrated scenarios where ctDNA-guided de-escalation strategies were cost-effective compared to "All ACT," including improved ACT treatment effect in ctDNA-positive patients, higher ctDNA positivity rates, enhanced ctDNA prognostic value, and/or reduced ctDNA testing costs.

Conclusion: ctDNA-guided strategies for ACT de-escalation are currently not cost-effective compared to an "All ACT strategy." One explanation is the non-negligible recurrence risk in ctDNA-negative patients. ctDNA-guided strategies could potentially become cost-effective if more than two ctDNA-related parameters improve simultaneously.

Background: Since the approval of immune checkpoint inhibitors (ICIs) in extensive-stage small-cell lung cancer (ES-SCLC) patients, immunotherapy has been commonly prescribed in first-line and sometimes in subsequent-line treatment in clinical practice. However, real-world data on ICIs in ES-SCLC remain limited.

Objectives: To delineate the current therapeutic landscape of ES-SCLC and assess the efficacy and outcomes of immunotherapy in different clinical settings.

Design and methods: Patients with ES-SCLC who received at least two lines of therapy from February 2020 to February 2024 were retrospectively recruited. All enrolled subjects were divided into two groups, namely "ICIs cohort" and "chemotherapy-only cohort" according to the treatment regimens they received in the entire disease course. Patients in the ICIs cohort who received immunotherapy as first-line treatment were analyzed separately from those who received it in later lines. Survival analysis was conducted to evaluate the clinical significance of ICIs in different treatment settings using the Kaplan-Meier method. The utility of thoracic radiotherapy was also evaluated in ES-SCLC patients. Multivariate Cox regression was applied to identify independent predictors of survival in ES-SCLC.

Results: A total of 214 patients were enrolled during the timeframe, of whom 81 received ICIs in first-line treatment and 78 received ICIs in subsequent-line treatment. In survival analysis, the ICIs cohort demonstrated significantly longer overall survival (OS) than the chemotherapy-only cohort, both in the first-line (17.0 vs 14.27 months; p = 0.045) and subsequent-line settings (16.87 vs 14.27 months; p = 0.017). In addition, the median OS was significantly prolonged in patients who underwent local thoracic radiotherapy compared to those who did not (20.53 vs 14.63 months; p = 0.005). Multivariate survival analysis validated that liver metastasis independently predicts inferior survival (p < 0.001). Meanwhile, immunotherapy administration (p = 0.002) and thoracic radiotherapy (p = 0.036) emerged as significant independent prognostic factors for prolonged survival in ES-SCLC patients.

Conclusion: The incorporation of immunotherapy, either in first-line or subsequent-line treatment, significantly improved survival outcomes in ES-SCLC. Notably, local thoracic radiotherapy retained its significant survival benefit in ES-SCLC in the immunotherapy era.

Background: Metastatic non-small-cell lung cancers (mNSCLC) harboring mutations in STK11 or KEAP1 are associated with an immunosuppressive tumor microenvironment and reduced responsiveness to PD-(L)1 inhibitor-based therapy, which is particularly notable when these genes are co-mutated with each other or with KRAS. Patients with these mNSCLC subtypes may benefit from combinations including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, aimed at enhancing immune responses.

Objectives: TRITON is an ongoing study comparing tremelimumab plus durvalumab and chemotherapy with pembrolizumab plus chemotherapy as first-line treatment for patients with non-squamous mNSCLC and mutations or co-mutations in STK11, KEAP1, or KRAS.

Design: Phase IIIb, multicenter, open-label, two-arm parallel randomized trial.

Methods and analysis: Approximately 280 eligible patients, aged ⩾18 years, will be randomized 1:1 to receive tremelimumab 75 mg plus durvalumab 1500 mg plus carboplatin AUC 5/6 or cisplatin 75 mg/m² and pemetrexed 500 mg/m² every 3 weeks (Q3W) for four cycles, followed by maintenance durvalumab 1500 mg plus pemetrexed 500 mg/m² Q4W, with an additional dose of tremelimumab 75 mg at week 16 and optional further dose at month 24; or pembrolizumab 200 mg plus carboplatin AUC 5/6 or cisplatin 75 mg/m² and pemetrexed 500 mg/m² Q3W for four cycles, followed by maintenance pembrolizumab 200 mg plus pemetrexed 500 mg/m² Q3W. Dual primary endpoints are overall survival (OS) in all randomized patients and OS in patients with STK11 or KEAP1 mutations or co-mutations. Key secondary endpoints include 12- and 24-month OS rates, progression-free survival, objective response rate, and safety. Enrollment is ongoing.

Ethics: TRITON will be approved by the independent ethics committee or institutional review board at each study site. All participants will provide written informed consent.

Discussion: Results will help to inform clinical practice and establish a biomarker-driven treatment strategy for these subtypes of mNSCLC with high unmet need.

Trial registration: ClinicalTrials.gov identifier: NCT06008093 (registration date: August 17, 2023).

Abscopal immunity-the regression of distant, non-irradiated lesions after localized radiotherapy (RT)-signals conversion of focal DNA damage into systemic antitumor immunity. This review advances a unifying three-stage framework-initiation, amplification, and reinforcement-explaining how RT can be leveraged to elicit durable systemic control. In initiation, immunogenic cell death and cytosolic DNA activate cGAS-STING (with TLR3-interferon (IFN)-I as a compensatory axis), driving dendritic cell recruitment and cross-priming in tumor-draining lymph nodes. Amplification entails chemokine-guided trafficking and expansion of CXCR3⁺ cytotoxic T cells, together with stromal and vascular remodeling that enable infiltration at out-of-field sites. Reinforcement reflects the balance between memory formation and adaptive resistance (PD-L1 upregulation, myeloid/Treg accrual, adenosine, and metabolic checkpoints), defining actionable targets for combinatorial intervention. We critically appraise clinical data showing that RT paired with immune-checkpoint inhibition can increase out-of-field control in selected settings, whereas heterogeneous or negative trials underscore the importance of dose and fractionation, field design/target coverage, RT-immune checkpoint inhibitor sequencing, and sparing of lymphoid structures. We outline emerging levers-including spatially fractionated RT, FLASH RT, proton therapy, myeloid- and adenosine-axis blockade, and nanotechnology-enabled in situ vaccination-and candidate biomarkers (interferon-response signatures, circulating tumor DNA kinetics, T-cell clonotypes). Operationalizing these principles points toward making the abscopal effect a predictable, clinically actionable endpoint rather than a rarity.